The purpose of this protocol is to study the biochemical, physiological and pharmacological control of extra-thyroidal conversion of thyroxine (T4) triiodothyronine (T3) and to determine the role of intrapituitary T3 production in the control of thyrotropin secretion. Pituitary T4-5'-monodeiodination will be studied in states of altered thyrotropin secretion induced by drugs, hormones, and iodine deficiency. Attempts will be made to purify this enzyme and to localize it within the cell, and its biochemical properties will be more extensively defined. The identity or dissimilarity of pituitary T4-5'-monodeiodinase with the hepatic and renal T4-5'-monodeiodinases will be established. The isolated perfused rat liver will be used to validate the results of liver homogenate experiments, to study the effects on T4 to T3 conversion of fuels and hormones requiring normal cellular organization for their effects and to study the rate of change of T3 content of liver nuclei in response to drugs and diseases. Analytical techniques include differential and density gradient centrifugation, enzyme solubilization with detergents, radioimmunoassay of iodothyronines and TSH, and spectrophotometric assay of tissue sulfhydryls. Clinical studies are planned to define the physiological implications of impaired T4 to T3 conversion. In patients suffering from non-thyroidal illness, the changes in the response of the pituitary to exogenous thyrotropin releasing hormone will be studied, and the nature of the alteration in thyroid hormone binding globulin (TBG) in human serum in illness will be assessed by comparison of immunoassayable TBG and the dialyzable fractions of T4 and T3. The unique responsiveness of anterior pituitary tissue to blood T4 observed in the rat will be investigated in hypothyroid patients given thyroxine acutely. The goal of these studies is the examination of factors regulating the production of T3 and the examination of the mechanisms by which T4 and T3 exert their effects on different tissues in man and animals.